Fractalkine (FKN) has been shown to contribute to microglial activation and in turn neurodegeneration in a number of neurological disorders including Alzheimer?s disease. We have been studying FKN and its contribution to neurodegeneration for a number of years and have demonstrated in multiple models a beneficial affect of FKN agonism. We show that over expression of a soluble form of FKN (sFKN) is capable of decreasing tau pathology in a tauopathy model, Tg4510. More importantly, we see significant reductions in brain atrophy and neuron loss. In AD a large reduction in FKN, has also been observed in cortical tissue from Alzheimer?s postmortem tissue. In Parkinson?s disease (PD) mice models, MPTP toxicity and a- synuclein over expression, we show that AAV-sFKN over expression, but not an AAV-mutant FKN (mFKN) that is resistant to shedding, can reduce disease pathology and neuron loss. Positive activity with the soluble versus the membrane bound FKN suggests that a soluble molecule has potential to activate the receptor and achieve neuroprotective effects. Thus FKN agonism is a potential therapeutic approach to treat AD and other neurological disorders such as PD. We propose a rigorous screening strategy consisting of a primary assay followed by a series of confirmatory and secondary assays that will refine the hit set, narrowing in on only those hits with desired properties. These desired properties include: a) concentration- responsive increase in b-arrestin recruitment to CX3CR1; b) specificity of action for the CX3CR1 receptor versus the unrelated CCR6 in a counter-assay that uses the same EFC- based detection system; and c) concentration-responsive inhibition of LPS-induced TNFa production in the neuronal cell line BV2. Collectively, these distinct but complimentary assay environments, detection formats and processes will ensure that the compounds arising from this effort are potent, selective agonists of CX3CR1. This study will lead to a novel therapeutic approach to treat AD, a disease that currently has no effective therapies.